This invention relates to N,N'-disubstituted guanidine analogues, and to compounds and pharmaceutical compositions comprising the same, which possess neuroprotective capability. This invention further relates to methods for treating any disease of the nervous system in which the pathophysiology of the disease involves excessive excitation of nerve cells by agonists of the N-methyl-d-aspartate (NMDA) receptor. Such excessive excitation can lead to dysfunction of the nervous system in the case of epilepsy and to nerve cell degeneration in cases of hypoxia, hypoglycemia, ischemia, trauma and in neurodegenerative diseases such as Huntington's chorea, Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease and Down's Syndrome.
A wide variety of substituted guanidines are disclosed in the patent literature. For example:
U.S. Pat. Nos. 1,411,731 and 1,422,506 discloses diphenylguanidine as a rubber accelerator; PA1 U.S. Pat. No. 1,597,233 discloses N-o-tolyl-N'-phenyl-guanidine as a rubber accelerator; PA1 U.S. Pat. No. 1,672,431 discloses N,N'-di-o-methoxyphenylguanidine as being useful for therapeutic purposes, especially in the form of water-soluble salts; PA1 U.S. Pat. No. 1,730,338 discloses N-p-dimethyl-amino-phenyl-N' -phenylguanidine as a rubber accelerator; PA1 U.S. Pat. No. 1,850,682 discloses a process for the preparation of disubstituted guanidine rubber accelerators bearing an additional substituent on the imine nitrogen atom; PA1 U.S. Pat. No. 2,145,214 discloses the use of disubstituted guanidines, e.g., diarylguanidines especially dixylylguanidine, as parasiticides; PA1 U.S. Pat. Nos. 2,254,009 discloses sym-di-2-octyl-guanidine and 2,274,476 and 2,289,542 disclose sym-dicyclohexylguanidine as insecticides and moth larvae repellents; PA1 U.S. Pat. No. 2,633,474 discloses 1,3-bis(o-ethylphenyl)guanidine and 1,3-bis(p-ethylphenyl)guanidine as rubber accelerators; PA1 U.S. Pat. No. 3,117,994 discloses N,N',N"-trisubstituted guanidines and their salts as bacteriostatic compounds; PA1 U.S. Pat. No. 3,140,231 discloses N-methyl- and N-ethyl-N'octylguanidines and their salts as antihypertensive agents; PA1 U.S. Pat. No. 3,248,246 describes (Example 5) a 1,3-disubstituted guanidine whose substituents are hydrophobic hydrocarbon groups, one of which is naphthylmethyl and the other is n-butyl; PA1 U.S. Pat. No. 3,252,816 discloses various N-substituted and unsubstituted cinnamyl-guanidines and generically the corresponding N'- and N"-alkyl substituted compounds and their salts as antihypertensive agents; PA1 U.S. Pat. No. 3,270,054 discloses N-2-adamant-1-yl- and N-2-homoadamant-1-yl-oxy-ethyl-thioethyl- and aminoethylguanidine derivatives bearing at most two lower alkyl groups on the N'- and/or N"-nitrogen atom as sympathicolytic and anti-viral agents; PA1 U.S. Pat. No. 3,301,755 discloses N-ethylenically unsubstituted- alkyl-guanidines and the corresponding N'- and/or N"-lower alkyl compounds as hypoglycemic and antihypertensive agents; PA1 U.S. Pat. No. 3,409,669 discloses N-cyclohexylamino-(3,3-dialkyl-substituted-propyl)-guanidines and the corresponding N'-alkyl- and/or N"-alkyl-substituted compounds as hypotensive agents; PA1 U.S. Pat. No. 3,547,951 discloses 1,3-dioxolan-4-yl-alkyl-substituted guanidines which have anti-hypertensive activity and discloses lower alkyl, including n-butyl, as a possible substituent on the other amino group; PA1 U.S. Pat. No. 3,639,477 discloses propoxylguanidine compounds as having anorectic properties; PA1 U.S. Pat. Nos. 3,681,459; 3,769,427; 3,803,324; 3,908,013; 3,976,787; and 4,014,934 disclose aromatic substituted guanidine derivatives wherein the phenyl ring can contain hydroxy and/or halogen substituents for use in vasoconstrictive therapy; PA1 U.S. Pat. No. 3,804,898 discloses N-benzycyclobutenyl and N-benzycyclobutenyl-alkyl-guanidines and the corresponding N-alkyl and/or N-alkyl-substituted compounds as hypotensive agents; PA1 U.S. Pat. No. 3,968,243 discloses N-aralkyl substituted guanidines and the corresponding N'-alkyl-nalkyl and N',N'-aralkyl compounds as being useful in the treatment of cardiac arrhythmias; PA1 U.S. Pat. No. 3,795,533 discloses o-halo-benzylidene-aminoidines and their use as anti-depressants for overcoming psychic depression; PA1 U.S. Pat. No. 4,007,181 discloses various N,N'-disubstituted guanidines substitutes on the imine nitrogen atom by a adamantyl as possessing antiarrhythmic and diuretic activities; PA1 U.S. Pat. No. 4,051,256 discloses N-phenyl- and N-pyridyl-N'- cycloalkyl-guanidines as antiviral agents; PA1 U.S. Pat. Nos. 4,052,455 and 4,130,663 disclose styrylamidines, as analgesics agents or for the prevention of blood platelet aggregation; PA1 U.S. Pat. No. 4,109,014 discloses N-hydroxysubstituted guanidines and the corresponding N-methyl disubstituted guanidines as vasoconstrictor agents; PA1 U.S. Pat. No. 4,169,154 discloses the use of guanidines in the treatment of depression; PA1 U.S. Pat. No. 4,393,007 discloses N-substituted and unsubstituted, N-substituted methyl-N'-unsubstituted, monosubstituted and disubstituted-N-unsubstituted and substituted guanidines as ganglionic blocking agents; and PA1 U.S. Pat. No. 4,471,137 discloses N,N,N'N"-tetraalkyl guanidines as being sterically hindered bases useful in chemical synthesis. PA1 U.S. Pat. No. 4,709,094 discloses 1,3-disubstituted-guanidines, e.g., 1-3-dibutyl-guanidine and 1,3 di-o-tolylquanidine, as sigma brain receptor ligands.
U.S. Pat. No. 1,795,738 discloses a process for the production of N,N'-dialkyl-di-substituted guanidines, including N-di-ethyl-N'-phenyl-guanidine, N-diethyl-N-isoamylguanidine, N-dimethyl-N'-isoamylguanidine and N-dimethyl-N'-ethylguanidine;
For examples of other substituted guanidines, see, e.g., U.S. Pat. Nos. 1,422,506; 1,642,180; 1,756,315; 3,159,676; 3,228,975; 3,248,426; 3,283,003; 3,320,229; 3,479,437; 3,547,951; 3,639,477; 3,784,643; 3,949,089; 3,975,533; 4,060,640 and 4,161,541.
Geluk, H. W., et al., J. Med. Chem., 12,712 (1969) describe the synthesis of a variety of adamantyl disubstituted guanidines as possible antiviral agents, including N,N'-di-(adamantan-1-yl)-guanidine hydrochloride, N-(adamantan-1-yl-N'-cyclohexyl-guanidine hydrochloride and N-(adamantan-1-yl)-N'-benzyl-guanidine hydrochloride.
We have found that certain N,N"-disubstituted guanidines possess high PCP receptor binding activity.
The amino acid L-glutamate is widely thought to act as a chemical transmitter substance at excitatory synapses within the central nervous system. Neuronal responses to glutamate are complex and appear to be mediated by at least three different receptor types, i.e., KA, QA and NMDA subtypes, each being named for their relatively specific ligands, i.e., kainic acid, quisqualic acid and N-methyl-D-aspartic acid, respectively. An amino acid which activates one or more of these receptor types is referred to as an excitatory amino acid (EAA).
The NMDA subtype of excitatory amino acid receptors is activated during normal excitatory synaptic transmission in the brain. Activation of NMDA receptors under normal conditions is responsible for the phenomena of long-term potentiation, a memory-like phenomenon, at excitatory synapses. Excessive excitation of neurons occurs in epileptic seizures and it has been shown that over-activation of NMDA receptors contributes to the pathophysiology of epilepsy.
NMDA receptors are also strongly involved in nerve cell death which occurs following brain ischemia. Upon the occurrence of ischemic brain insults such as stroke or heart attack, an excessive release of endogenous glutamate occurs, resulting in the over-stimulation of NMDA receptors. Associated with the NMDA receptors is an ion channel. The recognition site, i.e., the NMDA receptor, is external to the ion channel. When glutamate interacts with the NMDA receptor, it causes the ion channel to open, thereby permitting a flow of cations across the cell membrane, e.g., Ca.sup.2+ and Na.sup.+ into the cell and K.sup.+ out of the cell. It is believed that this flux of ions, especially the influx of Ca.sup.2+ ions, caused by the interaction of glutamate with the NMDA receptor plays an important role in neuronal death. See, e.g., Rothman, S. M. and Olney, J. W., Trends in Neurosci. 10(7), 299-302 (1987).
Agents which block responses to NMDA receptor activation therefore have therapeutic uses in the treatment of neurological disorders such as epilepsy and also in the prevention of nerve cell death resulting from hypoxia or hypoglycemia or following brain ischemia which occurs during stroke, trauma and heart attack. A number of disorders of the nervous system are associated with neurodegeneration that may be caused by over-activation of NMDA receptors. Antagonists of NMDA receptor-mediated responses have potential therefore for the treatment of such disorders as Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis and Down's Syndrome
Research on the NMDA receptor-ion channel complex has led to the determination of a receptor site within the ion channel known as the PCP receptor. See Vincent, J. P., Kartalovski, B., Geneste, P., Kamenka, J. M. and Lazdunski, M., Proc. Natl. Acad. Sci. USA 76, 4678-4682 (1979); Zukin, S. R. and Zukin, R. S., Proc. Natl. Acad. Sci. USA 76, 5372-5376 (1979); Sonders, M. S., Keana, J. F. W. and Weber, E., Trends in Neurosci. 11(1), 37-40
1988); and Anis, N. A., Berry, S. C., Burton, N. R. and Lodge, D., Br. J. Pharmacol. 79, 565-575 (1983). Compounds which bind to the PCP receptor can act as an ion channel block, thereby interrupting the flow of ions through the cell membrane. In this manner, agents which interact with the PCP receptor act as non-competitive blockers reducing the agonist action of glutamate at the NMDA receptor.
Known PCP receptor ligands include PCP [angel dust], i.e., phencyclidine, analogues such as 1-[1-(2-thienyl)-cyclohexyl]-piperidine (TCP), benzomorphane (sigma) opiates, dioxylanes and 5-methyl-10,11-dihydro- 5H-dibenzo[A,D]cycloheptene-5,10-imine (i.e., the drug MK-801, see U.S. Pat. No. 4,399,141). See, also, Wong, E. H. F., Kemp, J. A., Priestly, T., Knight, A. R., Woodruff, G. N., and Iversen, L. I., Proc. Natl. Acad. Sci. USA 83, 7104-7108 (1986). MK-801 is apparently the most potent selective PCP receptor ligand/NMDA channel blocker known to date.
We have identified compounds which exhibit a high activity for binding to the PCP receptor and are structurally different from known PCP ligands.